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Molecular & Cellular Proteomics 6:451-459, 2007.
© 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

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Research

An Antiproliferative Genetic Screening Identifies a Peptide Aptamer That Targets Calcineurin and Up-regulates Its Activity^*

Benoît de Chassey^,,¶, Ivan Mikaelian^,¶,||, Anne-Laure Mathieu, Marc Bickle, Delphine Olivier^,**, Didier Nègre^**, François-Loïc Cosset^**, Brian B. Rudkin and Pierre Colas^,,

From Aptanomics S.A., 181-203, avenue Jean Jaurès, 69007 Lyon, France, and Differentiation and Cell Cycle Group, Laboratoire de Biologie Moléculaire de la Cellule, UMR 5161 CNRS/Institut National de la Recherche Agronomique (INRA) U1237/Ecole Normale Supérieure Lyon and ^** INSERM U758, IFR128 "Biosciences Lyon-Gerland," Ecole Normale Supérieure, 46, allée d’Italie, 69364 Lyon cedex 07, France

Peptide aptamers are combinatorial recognition molecules that consist of a constant scaffold protein displaying a doubly constrained variable peptide loop. They bind specifically target proteins and interfere with their function. We have built a peptide aptamer library in a lentiviral expression system to isolate aptamers that inhibit cell proliferation in vitro. Using one of the isolated aptamers (R5G42) as a bait protein, we have performed yeast two-hybrid screening of cDNA libraries and identified calcineurin A as a target protein candidate. R5G42 bound calcineurin A in vitro and stimulated its phosphatase activity. When expressed transiently in human cells, R5G42 induced the dephosphorylation of BAD. We have identified an antiproliferative peptide aptamer that binds calcineurin and stimulates its activity. The use of this ligand may help elucidate the still elusive structural mechanisms of activation and inhibition of calcineurin. Our work illustrates the power of phenotypic screening of combinatorial protein libraries to interrogate the proteome and chart molecular regulatory networks.

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